Reduction of stent thrombogenicity

ABSTRACT

A tissue graft construct and method for repairing the inner linings of damaged or diseased vertebrate vessels is described. The method comprises the steps of positioning a tissue graft construct within a blood vessel at a site in need of repair. The tissue graft construct comprises a stent ( 3 ) covered with submucosal tissue ( 4 ) wherein the stent ( 3 ) is formed for receiving the distal end of a catheter ( 1 ) having an inflatable balloon ( 2 ).

FIELD OF THE INVENTION

[0001] This invention relates to an intestinal tissue covered prosthesisuseful in promoting the resurfacing and repair of damaged or diseasedtissue structures. More particularly this invention is directed tostents having a layer of submucosal tissue covering a surface of thestent, and their use in repairing damaged or diseased physiologicalvessels, particularly blood vessels.

BACKGROUND AND SUMMARY OF THE INVENTION

[0002] The most common cause of vascular disease in the Western world isatherosclerosis, in which cholesterol and fibrous tissue, often togetherwith calcium precipitates, gradually build up within the inner layers ofthe arterial wall, diminishing the cross sectional area available forblood flow. There are two essential abnormalities of suchatherosclerotic lesions that cause complications. The first is thenarrowing of the lumen, which produces a chronic limitation of bloodflow distally. The second is the abnormally raised, roughened innersurface of the artery, the physical properties of which tend to induceplatelet adhesion and clot formation at the diseased site. Thrombosiscan produce sudden cessation of blood flow with disastrous consequencesfor downstream organs such as the brain, heart muscle, kidney, or lowerextremities. The eroded, abnormal intimal surface of sclerotic vesselscauses additional complications including fragmentation ofatherosclerotic material with downstream embolization and hemorrhage ordissection of blood into the plaque itself causing sudden expansion ofthe lesion and occlusion of the vessel.

[0003] Percutaneous transluminal angioplasty (PTA), first performed 25years ago by Dotter and Judkins, is the technique of opening narrowed oroccluded blood vessels by passing guide wires and catheters through thestenotic or occluded portion of the blood vessel. Dotter's original PTAmethod involved inserting increasingly larger catheters over a guidewireto progressively dilate the vessel. Later modifications utilizedgraduated catheters with gradually tapering tips, which created morelateral compression and less longitudinal shearing action. These earlyPTA procedures were limited by the requisite stiffness of the cathetersand by the large puncture wounds required for the procedure.

[0004] In 1974, PTA procedures were revolutionized by the introductionof balloon catheter angioplasty. A balloon catheter has an expandablesac that can be expanded and contracted in a controlled manner inresponse to inflation pressure. Balloon catheter angioplasty involvespositioning the balloon catheter at a stenotic site and inflating thesac to a predetermined size to open the stenotic or occluded portion ofthe blood vessel. The sac is then deflated and the catheter removedleaving a larger lumen. Standard balloon angioplasty, with or withoutthe use of stents, produces a torn vessel with myointimal flaps andexposed fissures. These provide thrombogenic surfaces and sites forhemodynamic dissection. Furthermore, although the use of the stents inPTA procedures gives highly predictable immediate angiographic results,those stents all suffer the disadvantage that they have limited longterm efficacy. Despite holding the vessel open, the natural reparativeprocesses at a stent-dilated vessel result in healing tissues growingaround the stent structure and eventually occluding the lumen of thevessel. In addition to PTA procedures, alternative techniques forremoving atherosclerotic plaques include laser angioplasty andmechanical arthrectomy devices, which can vaporize, melt, or removeplaque material. However all such systems leave an abnormal,thrombogenic surface.

[0005] Angioplasty is now known to damage the vessel wall by tearing andstretching, and this form of controlled injury opens the vessel lumenand increases blood flow acutely in nearly all cases. However, abruptvessel closure during or immediately following PTA and late restenosiscontinues to limit the effectiveness of the procedure. To enhance theefficacy of PTA procedures catheters have been fitted with vascularstents.

[0006] Stents are three dimensional implantable structures that (upondelivery to an intra vessel position) physically hold a blood vesselopen. Vascular stents are typically formed to fit on the end ofconventional catheters for delivery of the stent to a predeterminedintravascular location. A number of stents for coronary use arecommercially available. They differ in physicochemical characteristicsand the mode of implantation. Ideally, a stent should be flexible,thrombo-resistant, low in profile, radiopaque, limit the expansion ofrepair tissues into the lumen of the vessel, and have an easy, reliabledelivery system. Currently available expandable stents can becategorized as “self expandable stents” and “balloon expandable stents.”Self-expanding stents utilize a spring mechanism to constrain the stentto a compressed shape. Upon removal of the constraint, the stent expandsto a predetermined dimension. Balloon expandable stents are expandablemembers formed to fit over a balloon catheter and capable of beingexpanded in response to controlled inflation of the balloon catheter.Inflation of the balloon results in plastic deformation of the stentbeyond its elastic limits so that the stent remains in its expandedstate upon subsequent deflation and removal of the balloon catheter.Preferably stents used in conjunction with PTA are “expandable stents”having an initial collapsed state that allows the stent to be deliveredto the desired intravascular location with minimal longitudinal shearingaction. Upon delivery to the desired location the stent is expanded tofix the stent at that location and to physically hold the vessel open.

[0007] The present invention utilizes a natural collagenous matrixcomprising submucosal tissue in combination with known angioplastictechniques to eliminate complications that derive from the residualabnormal, thrombogenic surfaces produced by current availableangioplastic techniques such as ordinary balloon angioplasty, laserangioplasty, and transluminal mechanical arthrectomy. The collagenousmatrices for use in accordance with the present invention comprisehighly conserved collagens, glycoproteins, proteoglycans, andglycosaminoglycans in their natural configuration and naturalconcentration. On preferred collagenous matrix comprises warm-bloodedvertebrate submucosa.

[0008] In accordance with the present invention the submucosa isisolated from warm-blooded vertebrate tissues including the alimentary,respiratory, intestinal, urinary or genital tracts of warm-bloodedvertebrates. The preparation of intestinal submucosa is described andclaimed in U.S. Pat. No. 4,902,508, the disclosure of which is expresslyincorporated herein by reference. Urinary bladder submucosa and itspreparation is described in U.S. Pat. No. 5,554,389, the disclosure ofwhich is expressly incorporated herein by reference. Stomach submucosahas also been obtained and characterized using similar tissue processingtechniques. Such is described in U.S. patent application No. 60/032,683titled STOMACH SUBMUCOSA DERIVED TISSUE GRAFT, filed on Dec. 10, 1996.Briefly, stomach submucosa is prepared from a segment of stomach in aprocedure similar to the preparation of intestinal submucosa. A segmentof stomach tissue is first subjected to abrasion using a longitudinalwiping motion to remove the outer layers (particularly the smooth musclelayers) and the luminal portions of the tunica mucosa layers. Theresulting submucosa tissue has a thickness of about 100 to about 200micrometers, and consists primarily (greater than 98%) of acellular,eosinophilic staining (H&E stain) extracellular matrix material.

[0009] Preferred submucosal tissues for use in accordance with thisinvention include intestinal submucosa, stomach submucosa, urinarybladder submucosa, and uterine submucosa. Intestinal submucosal tissueis one preferred starting material, and more particularly intestinalsubmucosa delaminated from both the tunica muscularis and at least thetunica mucosa of warm-blooded vertebrate intestine.

[0010] As a tissue graft, submucosal tissue undergoes remodeling andinduces the growth of endogenous tissues upon implantation into a host.It has been used successfully in vascular grafts, urinary bladder andhernia repair, replacement and repair of tendons and ligaments, anddermal grafts. The preparation and use of submucosa as a tissue graftcomposition is described in U.S. Pat. Nos. 4,902,508; 5,281,422;5,275,826; 5,554,389; and other related U.S. patents. When used in suchapplications the graft constructs appear not only to serve as a matrixfor the regrowth of the tissues replaced by the graft constructs, butalso promote or induce such regrowth of endogenous tissue. Common eventsto this remodeling process include: widespread and very rapidneovascularization, proliferation of granulation mesenchymal cells,biodegradation/resorption of implanted intestinal submucosal tissuematerial, and lack of immune rejection. The use of submucosal tissue insheet form and fluidized forms for inducing the formation of endogenoustissues is described and claimed in U.S. Pat. Nos. 5,281,422 and5,275,826, the disclosures of which are expressly incorporated herein byreference.

[0011] The present invention is directed to an improved prostheticdevice for repairing the intima surface of damaged or diseased vessels.The prosthetic devices of the present invention can also be used intraditional PTA procedures to open narrowed or occluded vessels. In oneembodiment the prosthetic device comprises a cylindrical shapedexpandable member having a luminal and exterior surface, and a layer ofsubmucosal tissue fixed to the exterior or luminal surface of themember. The expandable member is typically a stent wherein expansion ofthe stent increases the circumference of said member, thus fixing thedevice at a predetermined location within the vessel.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012]FIG. 1 is a cross-sectional view of a balloon catheter carrying asubmucosa tissue coated stent in accordance with this invention.

[0013]FIG. 2 is a sectional view of a submucosa covered stent positionedon a mandrel.

[0014]FIG. 3a-3 c are perspective views of a stent, wrappedlongitudinally with one or more sheets of submucosal tissue. FIG. 3aillustrates a stent, wrapped longitudinally with a single sheet ofsubmucosal tissue. FIG. 3c and FIG. 3d illustrate a stent wrapped withthree separate sheets of submucosal tissue, each sheet forming a singleloop of submucosal tissue, wherein the stent is shown in its condensedstate (FIG. 3c) or in its expanded state (FIG. 3d).

[0015]FIG. 4a and 4 b are perspective views of a tube of submucosahaving a plurality of longitudinal slits formed in the walls of thetube. FIG. 4a shows the tissue in its compact state and FIG. 4b showsthe tissue in its expanded state.

[0016]FIG. 5a-5 d illustrates the construction of one embodiment of asubmucosa covered stent.

[0017]FIG. 6a illustrates a stent wire covered with a narrow sheet ofsubmucosal tissue and FIG. 6b and FIG. 6c illustrate a stent formed fromthe submucosa tissue covered wire of FIG. 6a.

[0018]FIG. 7 illustrates an alternative embodiment of a submucosacovered wire for forming stents in accordance with this invention.

DETAILED DESCRIPTION OF THE INVENTION

[0019] The present invention is directed to an improved vascular stentcomposition and a method for repairing the inner linings of damaged ordiseased vessels. The method comprises the step of applying a new,non-thrombogenic intimal surface of submucosal tissue over the formerdamaged or diseased intima. The term “vessel” as used herein is definedas including any bodily canal, conduit, duct or passageway, includingbut not limited to blood vessels, bile ducts, the esophagus, thetrachea, the ureter and the urethra. In one embodiment the vessel isexpanded to increase the lumen of the vessel simultaneously with theapplication of a layer of submucosal tissue. Applicants have discoveredthat the applied submucosal tissue layer provides a non-thrombogenicsurface that induces the formation of a new endothelium and inhibitsrestenosis of a vessel after expansion of the vessel.

[0020] Submucosal tissue suitable for use in the present inventioncomprises naturally associated extracellular matrix proteins,glycoproteins, proteoglycans, glycosaminoglycans and other factors intheir natural configuration and natural concentration. Submucosal tissuecan be prepared from a variety of natural sources including thealimentary, respiratory, intestinal, urinary or genital tracts ofwarm-blooded vertebrates.

[0021] In one embodiment of the present invention the submucosal tissuecomprises intestinal submucosa delaminated from both the tunicamuscularis and at least the luminal portion of the tunica mucosa. Inanother embodiment the intestinal submucosal tissue comprises the tunicasubmucosa and basilar portions of the tunica mucosa including the laminamuscularis mucosa and the stratum compactum which layers are known tovary in thickness and in definition dependent on the source vertebratespecies.

[0022] The preparation of intestinal submucosal tissue for use inaccordance with this invention is described in U.S. Pat. No. 4,902,508.A segment of vertebrate intestine, preferably harvested from porcine,ovine or bovine species, but not excluding other species, is subjectedto abrasion using a longitudinal wiping motion to remove the outerlayers, comprising smooth muscle tissues, and the innermost layer, i.e.,the luminal portion of the tunica mucosa. One preferred source ofintestinal submucosa is the small intestine of mature adult pigsweighing greater than 450 lbs. The submucosal tissue is rinsed severaltimes with saline and optionally sterilized.

[0023] The submucosal tissue of the present invention can be sterilizedusing conventional sterilization techniques including glutaraldehydetanning, formaldehyde tanning at acidic pH, propylene oxide treatment,gas plasma sterilization, gamma radiation, electron beam radiation, andperacetic acid sterilization. Sterilization techniques which do notadversely affect the mechanical strength, structure, and biotropicproperties of the submucosal tissue is preferred. For instance, stronggamma radiation may cause loss of strength of the sheets of submucosaltissue. Preferred sterilization techniques include exposing the graft toperacetic acid, 1-4 Mrads gamma irradiation (more preferably 1-2.5 Mradsof gamma irradiation) or gas plasma sterilization; peracetic acidsterilization is the most preferred sterilization method.

[0024] Submucosal tissue treated with peracetic acid exhibits little ifany significant post-implantation calcification. The treatment istypically conducted at a pH of about 2 to about 5 in an aqueousethanolic solution (about 2 to about 10% ethanol by volume) at a peracidconcentration of about 0.03 to about 0.5% by volume. Typically, thesubmucosal tissue is subjected to two or more sterilization processes.After the submucosal tissue is sterilized, for example by chemicaltreatment, the tissue may be wrapped in a plastic or foil wrap andsterilized again using electron beam or gamma irradiation sterilizationtechniques.

[0025] The submucosal tissue specified for use in accordance with thisinvention can also be in a fluidized form. The preparation of fluidizedforms of submucosa tissue is described in U.S. Pat. No. 5,275,826, thedisclosure of which is expressly incorporated herein by reference.Fluidized forms of submucosal tissue are prepared by comminutingsubmucosa tissue by tearing, cutting, grinding, or shearing theharvested submucosal tissue. Thus pieces of submucosal tissue can becomminuted by shearing in a high speed blender, or by grinding thesubmucosa in a frozen or freeze-dried state to produce a powder that canthereafter be hydrated with water or a buffered saline to form asubmucosal fluid of liquid, gel or paste-like consistency.

[0026] The comminuted submucosa formulation can further be treated withan enzymatic composition to provide a homogenous solution of partiallysolubilized submucosa. The enzymatic composition may comprise one ormore enzymes that are capable of breaking the covalent bonds of thestructural components of the submucosal tissue. For example, thecomminuted submucosal tissue can be treated with a collagenase,glycosaminoglycanase, or a protease, such as trypsin or pepsin at anacidic pH, for a period of time sufficient to solubilize all or a majorportion of the submucosal tissue protein components. After treating thecomminuted submucosa formulation with the enzymatic composition, thetissue is optionally filtered to provide a homogenous solution.

[0027] The viscosity of fluidized submucosa for use in accordance withthis invention can be manipulated by controlling the concentration ofthe submucosa component and the degree of hydration. The viscosity canbe adjusted to a range of about 2 to about 300,000 cps at 25° C. Higherviscosity formulations, for example, gels, can be prepared from thesubmucosa digest solutions by adjusting the pH of such solutions toabout 6.0 to about 7.0.

[0028] Submucosal tissue can be stored in a hydrated or dehydratedstate. Lyophilized or air dried submucosa tissue can be rehydrated andused in accordance with this invention without significant loss of itsbiotropic and mechanical properties.

[0029] Submucosal tissue can be used in accordance with the presentinvention in combination with standard PTA devices to form prostheticdevices suitable for use in PTA procedures. Applicants anticipate thatthe use of the present tissue graft constructs comprising submucosaltissue will enhance the repair of damaged or diseased vessels and thusimprove the effectiveness of PTA procedures. The method of repairingvessels in vivo through the use of the disclosed devices comprises thesteps of contacting the intima surface of the vessel with submucosaltissue and holding the submucosal tissue in place to provide a newintima surface. Advantageously, the implanted layer of submucosal tissueinduces the growth of new endothelium without stenosis, and thereforethe submucosal tissue is preferably held in contact with the site inneed of repair for a time sufficient to induce the formation of a newintima surface. In preferred embodiments the tissue graft construct ispermanently located within a blood vessel or other structure and isultimately replaced by endogenous cell growth.

[0030] In one embodiment of the present invention submucosal tissue isused in combination with known angioplastic techniques and devices toprovide an improved composition and method for repairing damaged ordiseased portions of vessels. The improvement method comprises fixing agraft construct comprising submucosal tissue onto the surface of acatheter and delivering the tissue graft construct to a predeterminedintra-vessel location. It is anticipated that the vessel walls of anybodily vessel, conduit, canal or body cavity that is accessible to acatheter, can be repaired using the method described in the presentinvention.

[0031] Conventional catheters can be used to position the submucosalgraft constructs to an intra-vessel location for contact with a diseasedor damaged surface of the vessel. In accordance with one embodiment, thecatheter is a balloon catheter, and the balloon portion is covered withsubmucosal tissue. Upon positioning of the submucosal tissue coveredcatheter within a vessel, inflation of the balloon presses thesubmucosal tissue against the intima surface of the vessel. Subsequentdeflation of the balloon portion allows the removal of the catheter,leaving the submucosal tissue positioned in contact with the intimasurface of the vessel.

[0032] The submucosal tissue is preferably combined with additionalelements to enhance the retention of the submucosal tissue layer on theoriginal intima surface including, use of anchoring projections (such asplastic or metal pins), adhesives, stents, or other fixation devicesknown to those skilled in the art. In preferred embodiments thesubmucosal tissue is held in contact with the intima surface through theuse of a stent.

[0033] In accordance with one embodiment an improved stent is providedfor opening obstructed or occluded vessicles. The improved stentcomprises a conventional expandable stent, wherein the exterior surfaceof the stent is covered with submucosal tissue. Upon deployment of thesubmucosal tissue covered stent, the submucosal tissue covers theoriginal intima surface of the vessel to provide a smooth,non-thrombogenic surface. For example, in one embodiment the exteriorsurface of a stent is covered with submucosal tissue and a catheter isused to position the stent to a predetermined location in a bloodvessel. The stent is expanded, and thereby expands the lumen of thevessel, and the submucosal tissue is pressed against the luminal surfaceof the vessel thus covering the arteriosclerotic lesions and the surfaceof blood vessels damaged through the angioplasty procedure.

[0034] Table 1 provides a list of several stents suitable for use inaccordance with the present invention, however the list is notexhaustive and additional stents known to those skilled in the art canbe used in accordance with the present invention. TABLE 1 Design andCharacteristics of Stents in Clinical Evaluation Filament Filament StentStent Surface Stent Configuration Composition Thickness (mm) Diameter(mm) Length (mm) Area (%) Radiopaque Self-expanding Wallset Wire-meshStainless 0.07-0.10 3.5-6.0 21-45 18.5-20   No Steel Balloon- expandablePalmaz- Slotted tube Stainless 0.08 3.0-4.0 15 10 No Schatz SteelGianturco- Incomplete Stainless 0.15 2.0-4.0 20 10 No Roubin coil SteelWiktok Helical coil Tantalum  0.125 3.0-4.0 15-17  5-10 Yes StrekerWoven wire Stainless 0.07 2.0-3.5 15-25 — No steel/ Yes tantalum

[0035] In one embodiment, a prosthetic device utilizing a stentincorporates a conventional balloon angioplasty catheter around whichare placed, in order, an expandable vascular stent, and a layer ofsubmucosal tissue. Alternatively the stent can be sandwiched between twolayers of submucosal tissue (i.e., one layer covering the luminalsurface of the stent and one layer covering the external surface of thestent). The submucosal tissue is immobilized onto the stent through theuse of adhesives, sutures, interweaving the tissue with the stent strutsor other fixation techniques known to those skilled in the art.

[0036] The graft constructs of the present invention can be utilized incombination with conventional prosthetic devices known to those skilledin the art as being useful for vessel repair. For example the submucosaltissue constructs of the present invention are fixed onto the distal endof a prosthetic device, such as a catheter, using a variety oftechniques including: frictional engagement, applying the tissue ontothe surface of the prosthetic device followed by drying the material,suturing the tissue to the device, and other means known to thoseskilled in the art.

[0037] In one preferred embodiment, the graft construct comprises anexpandable cylindrical shaped member that has submucosal tissue coveringat least the external surface of the member. In this embodiment thelumen of the cylindrical member is sized for receiving the distal end ofa catheter, and more preferably the expandable member is formed tofrictionally engage the exterior surface of the distal end of thecatheter. The expansion of the expandable member increases thecircumference of the cylindrical shaped member thus fixing thesubmucosal tissue against the luminal surface of the vessel and allowingfor the removal of the catheter after deployment of the graft construct.

[0038] In one embodiment the catheter comprises a balloon-type catheterand the expandable member comprises a stent that is expanded to a fixedenlarged size by the inflation of the balloon catheter. In thisembodiment, inflation of the submucosal tissue/stent-covered ballooncatheter accomplishes several therapeutic objectives, almostsimultaneously. First, as in conventional balloon angioplasty, the lumenis forcibly dilated to reverse narrowing caused by an atheroscleroticplaque. Second, the vascular stent maintains the expanded caliber of thevessel, providing a degree of rigid support and maintaining a circular,isodiametric cross-sectional profile. In addition the stent, incombination with intra-arterial pressure, holds the submucosal tissueagainst the intima surface of the vessel covering any cracks, fissures,or tears in the vessel that result during balloon inflation. Suchdefects in blood vessels are highly thrombogenic when exposed to theblood stream. The new submucosal tissue also provides a barrier betweenthe metallic stent and vascular smooth muscle, inhibiting latere-stenosis. Finally, the submucosal tissue layer covers the old,diseased inner lining of the vessel (tunica intima), substituting asmooth, non-thrombogenic surface, into which healthy new endothelialcells can grow, ultimately replacing the submucosal tissue with newendothelium.

[0039] Commercially available stents that are best suited for use inaccordance with the present invention are metallic (typically stainlesssteel or tantalum) and are carried in a collapsed form over aconventional balloon angioplasty catheter. When the balloon is inflatedthe stent is deployed and expanded to its working, in vivo size.However, other types of stents, such as self-expanding stents, can alsobe used in accordance with the present invention to resurface damaged ordiseased body vessels.

[0040] One submucosal tissue covered stent construct suitable for use inthe present invention comprises a stent having one or more pieces ofsubmucosal covering the exposed external surfaces of the stent. Uponimplantation into a host the submucosal tissue is held between the stentand the diseased vessel wall. In one preferred embodiment the stent ispositioned to the desired location in the vessel through the use of aballoon-type catheter. In this embodiment shown in FIG. 1, a singlelumen angioplasty catheter 1 having an inflatable balloon 2, which issemi-rigid or rigid upon inflation, carries a vascular stent 3 coveredwith small intestinal submucosa 4. This embodiment of the invention isintended for segments of vessels without significant side branches, suchas the renal arteries, the common carotid arteries, or the poplitealarteries. Because of the absence of significant side branches, the lackof perforations in the submucosal tissue will not pose problems fortissue perfusion.

[0041] In another embodiment (FIG. 2) the submucosal tissue 12 overlaysboth the luminal surface 18 and the exterior surface 20 of the stent 10to covered all stent surfaces with submucosal tissue 12. Such asubmucosal tissue covered stent is prepared in accordance with oneembodiment by first preparing a tubular submucosal tissue construct,longer than the stent (preferably twice as long as the stent). A mandrel26 of the appropriate size is inserted into the lumen of a tube ofsubmucosal tissue and the stent 10 is then fashioned around thesubmucosal tissue 12. The leading edge 14 and trailing edge 16 ofsubmucosal tissue 12 are inverted, brought back over the exteriorsurface 20 of the stent 10 and sutured together, as shown incross-section in FIG. 2. In this embodiment, wherein both the luminalinward and exterior 20 surfaces of the stent are covered with submucosaltissue, a lumen 28 is formed between the outer and inner layers of thesubmucosal tissue. The lumen 28 can optionally be filled with fluidizedsubmucosal tissue, growth factors, a heparin containing composition orother components to assist the repair of the damaged or diseased vessel.

[0042] The tube of submucosal tissue used to prepare the submucosacovered stents of the present invention can be prepared in accordancewith procedures described in U.S. Pat. No. 5,902,508. In one embodimenta tube of submucosa tissue is prepared from intestinal submucosa thathas been delaminated from both the tunica muscularis and at lest theluminal portion of the tunica mucosa. The appropriate sized lumen of thetube of submucosa can be prepared by inserting a glass rod/mandrel,having the appropriate diameter, into the lumen of the tube of submucosaand gathering up the redundant tissue and suturing longitudinally alongthe gathered material.

[0043] Alternatively, a sheet of submucosa can be used to form the tubeof submucosal tissue. In one embodiment the sheet of submucosal tissueis rolled up around the distal end of the catheter and the opposinglateral ends are situated to form a tube that frictionally engages thecatheter. Alternatively the graft construct can be formed to define atube of submucosa having a diameter approximately the same as thecatheter by wrapping the submucosal tissue around an appropriately sizedmandrel. The formed tube of submucosal tissue can then be fixed onto thedistal end of a catheter. The tube of submucosal tissue is held in itscylindrical shape by sutures, adhesives, compressing the tissue underdehydration conditions, heat treating the tissue, the use ofcrosslinking agents or any combination thereof. In one embodimentmultiple strips of submucosal tissue are overlapped with one another asthey are wrapped onto the mandrel to form a multi-layered tube ofsubmucosal tissue. In accordance with the present invention thesubmucosal tissue can be wrapped onto the mandrel in a variety ofdifferent orientations, provided that no gaps exist between the seams ofoverlapped tissue that would expose the surface of the mandrel.

[0044] In one embodiment a submucosal tissue covered stent construct isformed by wrapping the stent with one or more strips of submucosal tocover both the luminal and the exterior surfaces of the stent. Forexample, a single long narrow sheet of submucosal tissue 36 can bewrapped longitudinally along the exterior surface of the stent 38starting at one end of the stent, running along the exterior surface tothe second end of the stent and then running along the luminal surface,from the second end back to the first end (See FIG. 3a). Thelongitudinal wrapping is continued forming continuous loops ofsubmucosal tissue that cover the luminal and exterior surfaces of thestent 38. In one preferred embodiment the strip of submucosal tissue iswrapped longitudinally so that each loop overlaps with the previouslyunderlying strip. The overlapped region may range from about 20% up toabout 75%. The width of the individual strips and the amount of overlapwill vary according to the size and type of stent selected. In addition,the stent can optionally be covered with additional strips of submucosaltissue to increase the thickness of the submucosal layer. Theappropriate parameters (width of the sheet of submucosal tissue andpercent overlap) will be selected to ensure that upon deployment of thestent 38 the stent surface will not become exposed. Accordingly, uponexpansion of the circumference of the stent the individual loops ofoverlapped submucosal tissue will slide over one another to allow forthe increased size of the stent without exposing the surface of thestent

[0045] In one embodiment the luminal and exterior surfaces are coveredby a single strip of submucosal tissue, wherein the strip of submucosaltissue has a width less than the circumference of the stent. The stripof submucosal tissue is longitudinally wrapped about the exterior andluminal surfaces to form loops of submucosal tissue that cover theentire surface of the stent. Preferably the loops of submucosal tissuewill overlap with each other to such an extent that the stent can beexpanded to its in vivo working size without exposing the surface of thestent.

[0046] In another embodiment (FIG. 3b) both the luminal surface an theexterior surface of the stent are covered by a plurality of separatesheets of submucosal tissue, each of which are wrapped longitudinallyabout the exterior and luminal surface of the stent to form loops ofsubmucosal tissue. As shown in FIG. 3b and 3 c three sheets ofsubmucosal tissue each having a first end 70 and a second end 72 arelongitudinally wrapped around the luminal and exterior surface of thestent and the first and second ends (70 and 72, respectively) aresutured together to form 3 separate loops of submucosal tissue. In thecollapsed form shown in FIG. 3b the stent has a collapsed luminaldiameter CD and the three sheets of submucosal tissue overlap oneanother by an overlap region, OR₁. When the stent is deployed thediameter of the stent lumen is expanded to a second diameter, ED,wherein ED is greater than CD. (See FIG. 3c). The sheets of submucosaslide past one another to account for the increase in the circumferenceof the expanded stent and the overlapped region decreases in size to adistance OR₂ wherein OR₁, is greater than OR₂. Hence, both the inwardand outward facing surfaces of the stent remain covered with submucosaltissue, and both the blood and underlying vascular wall “see” onlysubmucosal tissue. Alternatively in one embodiment the individual loopsof submucosal tissue shown in FIG. 3c and FIG. 3d cover only theexterior surface of the stent, and the two opposite ends of each sheetof submucosal tissue are looped around the first and second end coil,respectively, of the stent and sutured.

[0047] Applications involving the repair of vessels that have severalbranches (such as the left anterior descending coronary artery, that hasseveral smaller, but metabolically significant side branches) requiresmodification of the basic device. In accordance with FIG. 4a and 4 b, asleeve of submucosal tissue 30 is placed over a stent, and the tissuecovered stent is placed over an angioplasty balloon. Staggered rows oflongitudinal slits 32 are cut in the submucosal tissue, as shown in FIG.4a. When the balloon-stent unit is expanded, the submucosal tissue opensto form a submucosal tissue mesh 34, through which blood can pass fromthe central lumen into side branches (FIG. 4b).

[0048] The mesh provides a matrix for in growth of native endothelialtissue, however high blood flow rates through the open spaces in themesh where vessel side branches exist will tend to retard thrombosis,maintaining the opening in the submucosal mesh. Occasional obstructionof a side branch by the substance of the mesh can occur, but byoptimizing mesh size, blood flow to the side branches will be preserved.

[0049] Attachment of the slit submucosal tissue to the coils of theunderlying stent is accomplished by the placement of sutures throughadjacent slits in the tissue and around individual stent coils to formgathers of submucosal tissue. As the balloon stent complex is expandedin vivo, the meshwork opens to the pre-planned final diameter, and thegathers are drawn taut.

[0050] Alternatively, a slitted tube of submucosal tissue can be used tocover both the exterior and luminal surface of the stent to repairvessels that have several branches. In this embodiment, a slitted sheetof tubular submucosal tissue, twice as long as the stent, is laid downover the surface of a mandrel, and a stent is fashioned around it. Thenthe leading and trailing edges of slitted submucosal tissue are everted,brought back over the exterior surface of the stent and sutured togetherto secure the submucosal tissue around both the blood-facing andtissue-facing surfaces of the stent. In this case suturing thesubmucosal tissue to the individual coils of the stent is not necessary,the single suture line is sufficient to secure the submucosal tissue inplace. The stent can be fixed onto the distal end of a balloon typecatheter and when the balloon stent complex is expanded in vivo, themeshwork opens to allow blood to pass from the central lumen into sidebranches.

[0051] Deployment of a submucosal tissue-covered stent, corrects tworesultant abnormalities of atherosclerotic occlusive disease in onesimple mechanical treatment. First, angioplasty with stent placementreverses the chronic stenosis caused by atherosclerotic plaque material.Second, resurfacing with anchored submucosal tissue covers the old,complication prone, diseased surface with a smooth, fresh, biocompatiblesurface that is resistant to thrombosis, fragmentation, and dissection.Furthermore, submucosal tissue can be dried, stored, and rehydratedwithout loss of mechanical strength or thromboresistance. Thussubmucosal tissue can be applied to angioplasty catheters, and stored inconventional sterile packages., and rehydrated at the time of use byimmersion in sterile saline.

EXAMPLE 1 Preparation of a Submucosal Tissue Covered Stent

[0052] A segment of intestinal tissue (the proximal jejunum) from thedonor species of choice is collected within 1 to 3 hours of death. Thesubmucosal tissue, prepared as described in U.S. Pat. No. 4,902,508, issized to make the diameter of the implant less than or equal to thenormal caliber of expected recipient blood vessel (i.e., isodiametric).A sterile glass rod having the same diameter as that of the targetvessel is selected and placed into the graft lumen. This reduceddiameter allows for the initial 10 to 20% dilation that occurs afterexposure to the systemic circulation and eventual isodiametric size.Redundant tissue is then gathered and the desired lumen diameterachieved by using either two continuous suture lines or a simpleinterrupted suture line with 5-0 polypropylene suture material with aswaged, tapercut needle. The material is then fixed onto the pre-madestent-and-balloon catheter and the cut longitudinal ends are tuckedunder the ends of the stent or otherwise secured to the stent, forexample by suturing the submucosa to the individual coils of the stent(See FIG. 1). The preferred stent design is one that does not changelength during deployment, and thus does not create longitudinal folds orwrinkles in the submucosal tissue.

EXAMPLE 2

[0053] Submucosal tissue can be fixed onto a stent by interweaving thesubmucosal tissue onto the individual coils of a wire stent as shown inFIG. 5a. First the stent 43 is made from a single wire 44 that is bentback and forth to form a coil, as shown in FIG. 5a A sheet of drysubmucosal tissue sheet 42 is then interweaved with the zig-zag shapedstent wires as shown in FIG. 5a. A first end of the submucosal tissue 46is sutured to one end of the stent wires 46, whereas the opposite freeend 48 extends beyond the unsutured end of the stent wires as shown inFIGS. 5a and 5 c. Then the submucosal tissue-coated stent wires are bentinto a cylindrical shape to form an incomplete tube, as shown in FIGS.5b, 5 c and 5 d. FIG. 5b is an exploded view illustrating theinterweaving of the coiled stent with the submucosal tissue. FIG. 5cillustrates the complete construct and FIG. 5d provides a sectional viewof the submucosal tissue covered stent. Note that the opposite free end48 extends beyond the coils of the stent 40 so that when the stent isexpanded in the blood vessel, there is enough submucosal tissue to fullycover the stent. FIG. 5b shows how the stent wires interweave.

EXAMPLE 3

[0054] In an alternative embodiment the submucosal tissue is fixed tothe stent by spiral wrapping sheets of submucosal tissue on a stent wire(See FIG. 6a), then forming the stent, as shown in FIG. 6b and 6 c. Thestent is made by starting with a straight stent wire 50 which is coveredwith submucosal tissue. The wire is covered with two or more strands ofdry submucosal tissue 52 by braiding as shown in FIG. 6a. When coveredin this way, the submucosal tissue is wetted and allowed to dry.Therefore the strands of submucosal tissue form a braided sleeve thatcovers the wire. Alternatively the stent wire can be coated with afluidized form of submucosal tissue and allowed to dry. The wire is bentinto a stent as shown in FIGS. 6b and 6 c.

[0055] The submucosal tissue can also be fixed onto the stent wirewithout first cutting a prepared tube of submucosa into narrow sheets ofsubmucosa. After preparing a tube of submucosal tissue as described inU.S. Pat. No. 4,902,508, the stent wire 62 is passed through the lumenof the prepared tube of submucosal tissue 60 (FIG.7). The tube ofsubmucosal tissue 60 will then be stretched by pulling the two ends awayfrom each other, to decrease the diameter of the prepared tube ofsubmucosal tissue, thereby forming a closely fitting covering for thestent wire, as shown in FIG. 7. The gut-covered stent wire is thencoiled as in FIG. 6b to form the expandable stent.

EXAMPLE 4 Implantation of Submucosa Covered Stents within Dogs

[0056] Five dogs (hounds, approximately 40 to 60 lbs) will undergo alaparotomy under general anesthesia (Pentothal I.V. and Isoflurane gasmaintained at 2%) with placement of a 2-4 cm, small intestinal submucosacoated, 11.5 Fr. biliary stent. The stents will be Cotton Leung BiliaryStents manufactured by Wilson-Cook Medical, Inc. of Winston-Salem, N.C.Sterilized small submucosa is prepared in accordance with Example 1 intubular form and having a length greater than the length of the stent.The submucosal tissue is positioned within the luminal space of a stentso the two ends of the submucosal tissue extend past the ends of thestent. The two ends of the submucosal tissue will then be everted andpulled back over the exterior portion of the stent and sutured at themidline of the stent. Thus both the exterior and luminal surface of thestent will be covered with the submucosal tissue.

[0057] This submucosal tissue covered stent is then deployed in the bileduct of the dogs using the following procedure which entails alaparotomy in the dog under general anesthesia. A midline incision fromumbilicus to xiphisternum will be performed with dissection to andopening of the peritoneum performed in accordance with procedures knownto those skilled in the art. The common bile duct will be identified andfollowed to the duodenum. A duodenotomy will be performed and the majorpapilla identified. After dilation of the papilla, a 24 cm submucosaltissue coated 11.5 Fr biliary stent will be placed into the common bileduct with the distal portion of the stent protruding through the papillaand draining into the duodenum. The duodenotomy and abdominal wallincisions will be closed and the animal allowed to recover fromanesthesia in an intensive care cage. The dogs will be monitored by theMedical Research Lab Animal Technicians and be allowed food and waterapproximately 24 hours post-operatively. Post-operative analgesia(torbutrol) will be administered as required.

[0058] No drains will be placed in the animals and the post-operativerecovery needs are expected to be those encountered with exploratorylaparotomy alone. Animals will be observed for signs of sepsis,jaundice, bowel obstruction, etc. and euthanized at this time ifnecessary. Euthanasia will be by Socumb euthanasia solution, I.V., 1ml/10 lbs. Dogs with uneventful post-operative courses will beeuthanized at approximately 12 weeks; the biliary stent will berecovered at the time of postmortem examination of the abdomen withappropriate specimens of adjacent organs submitted for pathologicalexamination.

1. A prosthetic device for repairing the inner linings of damaged ordiseased vertebrate vessels, said device comprising a cylindrical shapedexpandable member having a luminal and exterior surface, whereinexpansion of said member increases the circumference of said member; anda layer of submucosal tissue fixed to the luminal or exterior surface ofsaid member.
 2. The device of claim 1 wherein the cylindrical shapedmember is a vascular stent having a lumen sized for receiving acatheter.
 3. The device of claim 1 wherein the submucosal tissuecomprises intestinal submucosa delaminated from both the tunicamuscularis and at least the luminal portion of the tunica mucosa of awarm-blooded vertebrate.
 4. The device of claim 3 wherein the submucosaltissue covers both the exterior and the luminal surface of the stent. 5.The device of claim 4, wherein said layer of submucosal tissue comprisesa narrow sheet of submucosal tissue wrapped longitudinally about theluminal and exterior surface of the stent a plurality of times to formloops of submucosal tissue wherein each loop partially overlaps anotherloop of submucosal tissue.
 6. The device of claim 4, wherein the layerof submucosal tissue comprises a plurality of narrow sheets ofsubmucosal tissue having a first end and a second opposite end wrappedlongitudinally about the luminal and exterior surface of the stent,wherein the first and second opposite ends of each sheet of submucosaltissue are bonded together to form loops of submucosal tissue andwherein each loop of submucosal tissue partially overlaps another loopof submucosal tissue.
 7. The device of claim 2 wherein the means forexpanding the stent comprises a releasable spring mechanism that biasesthe prosthetic device to a minimal circumference.
 8. The device of claim2 wherein the layer of submucosal tissue comprises fluidized submucosaltissue coated onto the surface of the stents.
 9. The device of claim 2wherein the submucosal tissue covering the stent is provided with aplurality of slits that upon expansion of the expandable member providefluid communication between the lumen of the stent and the exterior ofthe stent.
 10. A method for repairing the inner linings of damaged ordiseased vertebrate vessels, said method comprising the steps of:inserting a catheter into a vessel, wherein said catheter has a graftconstruct comprising submucosal tissue of a warm blooded vertebrateremovably fixed to its distal end; positioning the graft construct at asite within the vessel in need of repair; biasing the graft constructagainst the luminal surface of the vessel to fix the graft construct tothe luminal surface; and removing the catheter.
 11. The method of claim10 wherein the catheter is a balloon-expandable catheter and the step ofbiasing the graft construct comprises inflating the balloon.
 12. Themethod of claim 10 wherein graft construct further comprises a stent,and the submucosal tissue covers at least a portion of the exteriorsurface of the stent.
 13. The method of claim 10 wherein the vessel is ablood vessel.
 14. An improved vascular stent for expanding obstructedvessels, said stent formed as an expandable tube having an exterior andluminal surface, the improvement comprising fixing a layer of submucosaltissue to the external surface of the stent.
 15. The improved vascularstent of claim 14 further comprising a layer of submucosal tissuecovering the luminal surface of the stent.
 16. The improved vascularstent of claim 14 wherein a strip of submucosal tissue is wrappedlongitudinally about the luminal and exterior surfaces of the stent aplurality of times to form loops of submucosal tissue and wherein eachloop of submucosal tissue partially overlaps an adjacent loop ofsubmucosal tissue.
 17. The improved vascular stent of claim 14 whereinthe layer of submucosal tissue is formed as a tube of submucosal tissue,wherein the tube is provided with a plurality of longitudinal slits. 18.The improved vascular stent of claim 17 wherein the longitudinal slitsare approximately uniform in shape and are located equidistant from oneanother.
 19. The device of claim 14, wherein the layer of submucosaltissue comprises a pluraltiy of narrow sheets of submucosal tissuehaving a first end and a second opposite end wrapped longitudinallyabout the luminal and exterior surface of the stent, wherein the firstand second opposite ends of each sheet of submucosal tissue are bondedtogether to form loops of submucosal tissue and wherein each loop ofsubmucosal tissue overlaps with another loop of submucosal tissue. 20.The improved vascular stent of claim 14 wherein the stent comprises awire that is coiled and shaped in the form of an incomplete tube, andthe submucosal tissue is fixed to the stent by braiding a plurality ofnarrow sheets of submucosal tissue around the wire forming the stent.